Modafinil (C15H15NO2S), is 2-(benzhydryl-sulfinyl)acetamide, and is also known as 2-[(diphenylmethyl) sulfinyl] acetamide.
Modafinil has been described as presenting a “neuropsychopharmacological spectrum characterized by the presence of excitation with hyperactivity and of hypermotility; and by the absence of stereotypy (except in high doses) and of potentialization of the effects of apomorphine and amphetamine” (U.S. Pat. No. 4,177,290; hereinafter the “'290 patent,” which is incorporated in its entirety herein by reference). A single administration of modafinil results in increased locomotor activity in mice and increased nocturnal activity in monkeys (Duteil et al., Eur. J. Pharmacol. 180:49 (1990)). Modafinil has been successfully tested in humans for treatment of idiopathic hypersomnia and narcolepsy (Bastuji et al., Prog. Neuro-Psych. Biol. Psych. 12:695 (1988)).
Other uses of modafinil have been presented. U.S. Pat. No. 5,180,745, incorporated in its entirety herein by reference, discloses the use of modafinil for providing a neuroprotective effect in humans, and in particular for the treatment of Parkinson's disease. The levorotatory form of modafinil, i.e., (-)benzhydrylsulfinyl-acetamide, may have potential benefit for treatment of depression, hypersomnia and Alzheimer's disease (U.S. Pat. No. 4,927,855, incorporated in its entirety herein by reference). European Published Application 547952 (published Jun. 23, 1993) discloses the use of modafinil as an anti-ischemic agent. European Published Application 594507 (published Apr. 27, 1994) discloses the use of modafinil to treat urinary incontinence.
Preparations of modafinil having a defined solid particle size have been described in U.S. Pat. No. 5,618,845, incorporated in its entirety herein by reference, and preparations of a levorotatory isomer of modafinil was described in U.S. Pat. No. 4,927,855. Heterocyclic derivatives of modafinil are disclosed in U.S. Patent Application No. 60/204,789, incorporated in its entirety herein by reference.
Modafinil has been approved for use in humans in 100 mg and 200 mg solid unit dose forms in the U.S. It is also desirable to formulate modafinil in liquid compositions. It has been observed that modafinil has very poor water and lipid solubility and it is therefore difficult to solubilize modafinil in pharmaceutically-acceptable compositions. Conventional solid and liquid formulations that include modafinil are described in the '290 patent. Liquid suspensions or emulsions of modafinil were mentioned in U.S. Pat. No. 5,618,845. A suspension of modafinil was reported in U.S. Pat. No. 5,180,745. An aqueous cyclodextrin solution of modafinil was described in Rambert, F. A., et al. Neuropsychopharmacology, 10(3S), Part 2 (May 1994).
A technique recently developed to formulate liquid pharmaceutical compositions for agents that display very low water solubility involves a self-emulsifying drug delivery system, known as “SEDDS”. These drug delivery systems are isotropic mixtures of lipids or lipid-soluble compounds and a surfactant that rapidly form thermodynamically stable microparticles upon contact with water. See, e.g., Shah et al., International Journal of Pharmaceutics (Netherlands), 106:15-23, (1994), which is incorporated in its entirety herein by reference.
Despite the low lipid solubility of modafinil, it has been discovered that modafinil can be formulated to produce particle-forming compositions, wherein the compositions are capable of forming particles comprising a modafinil compound upon contact with water. These compositions have been found to effectively solubilize modafinil in an aqueous component and to provide for effective bioavailable delivery of modafinil to a subject in need thereof.